Project Summary Parasitic nematodes infect over 1.5 billion people and pose a major challenge to human health and socioeco- nomic development in endemic countries. This tremendous global disease burden is partly curtailed by mass drug administration (MDA) programs that depend on the continued ef?cacy of a small number of anthelmintic drugs. Parasite resistance to anthelmintic chemotherapy is widespread in veterinary medicine and constitutes a signi?cant and emerging threat in human medicine. The early detection of resistance-associated alleles in nematode parasite populations is critical to the goal of slowing anthelmintic resistance and extending drug lifes- pan. This goal is currently hampered by our inadequate understanding of the genetic and molecular mechanisms that underlie anthelmintic resistance in parasitic nematodes. The experimental intractability of human nema- tode parasites necessitates the development of new approaches to discover and validate relevant markers for resistance. Benzimidazoles and avermectins comprise essential classes of broad-spectrum anthelmintics, and human-approved formulations of these drugs are mainstays in the treatment of intestinal and ?larial nematode infections. I have mapped quantitative trait loci (QTL) associated with avermectin and benzimidazole resistance using an innovative high-throughput whole-genome statistical genetics pipeline in the powerful model nematodes Caenorhabditis elegans and Caenorhabditis briggsae. These data reveal a complex multigenic basis for aver- mectin resistance and implicate an exciting and entirely novel small RNA-mediated mechanism for benzimidazole resistance. I propose to narrow these genomic loci to resolve undiscovered protein-coding and RNA genes that robustly and causally contribute to anthelmintic resistance. My central hypothesis is that these model nematode systems can be used to identify new genetic mechanisms and loci that are predictive of anthelmintic resistance in medically important parasitic nematodes. To test whether determinants of anthelmintic resistance are appreciably conserved, putative genetic markers identi?ed in C. elegans will be experimentally validated in the mosquito-borne human ?larial parasite Brugia malayi, an etiological agent of lymphatic ?lariasis, and the soil-transmitted intesti- nal nematode Ascaris suum. Upon completion, this project will provide fundamental new data on novel genetic mechanisms of nematode avermectin and benzimidazole resistance, and produce a set of validated markers that can be used to monitor anthelmintic resistance in human nematode parasites to help ensure the future success of chemotherapy-based helminth control.